Carotid Intima Media Thickness: A Measurement for Cardiovascular Risk and its Association with Hormone Deficiencies

Bronner Handwerger, ND

Assessing cardiovascular risk factors is always part of the naturopathic intake. The question arises as to how we assess these risks. We recognize that traditional markers like cholesterol, HDL, LDL, Lp(a), fibrinogen, homocysteine and even cardio CRP provide us with valuable information, along with family history. Although these are important to assess, they still do not give us the kind of reliable information we are looking for.

Cardiovascular disease is the No. 1 killer in the U.S. for both men and women. Heart disease and stroke account for almost six million hospitalizations each year, and more than 40% of all people age 45 and older have some form of cardiovascular disease. Approximately 1.1 million Americans are expected to have a new or recurrent heart attack this year, and 60% of all deaths in the U.S. are attributed to cardiovascular disease. A more sobering statistic is that 40%-50% of all heart attack patients have a “normal” cholesterol or lipid profile, which illustrates that our current measures for assessing these risks is inadequate. How many times have you heard the story, “he just had a stress test and passed with flying colors?”

This is why I have begun to use carotid intima media thickness (CIMT) measurements as part of my routine workup to screen patients.

About CIMT

CIMT is a new, noninvasive ultrasound test being recommended by the American Heart Association and the American College of Cardiology to screen for heart disease in apparently healthy individuals age 45 or older. If risk factors are present, I recommend this screening beginning at age 40.

The test is performed with a high-resolution B-mode ultrasound transducer. It is safe, painless and takes about ten minutes to complete.

Looking at the carotid arteries provides a “window” to the coronary arteries. Not only do they have similar risk factors but, more importantly, the relationship between the atherosclerotic burden in a carotid artery and in a coronary artery is the same as between any two coronary arteries. Thus, carotid atherosclerosis provides a window to the degree of coronary atherosclerosis in an individual. CIMT is an independent predictor of future cardiovascular events, including heart attacks, cardiac death and stroke.

The value of CIMT tends to increase with age. Published studies of CIMT measurements in patients ages 45 to 65 have made it possible to develop a reference range of what is “normal” at different ages. From the test, a report is generated that tells us a patient’s vascular age. If the vascular age matches or is younger than the patient’s chronological age, that patient has a lower risk for heart disease. If the vascular age exceeds the patient’s chronological age, it alerts us to be more aggressive at controlling those risk factors associated with heart disease for this patient.

Importantly, with various therapies it is possible to achieve regression or slow progression of the CIMT. A follow-up CIMT should be performed six months to a year after therapy is initiated to evaluate the therapy’s effectiveness.

Androgens and Cardiovascular Disease

There is increasing evidence of a direct association between normal androgen levels and reduced cardiovascular morbidity and mortality in both men and women.

In both sexes, circulating androgen levels decline with advancing age. In the population-based Rotterdam study, an independent inverse association between levels of testosterone and aortic atherosclerosis was found.

New research suggests that one out of four men older than age 30 have low testosterone levels, but only one out of every 20 men have clinical symptoms linked to such a deficiency. This means that 25% of the men walking into our offices are at risk.

Low testosterone is defined as 300ng/dL of total testosterone and less than 5ng/dL of free testosterone in men. Based on these results, researchers predict that by 2025 there may be as many as 6.5 million American men between 30 and 79 years of age with symptomatic androgen deficiency, an increase of 38% from the year 2000 population estimates.

Another study from The Journal of Clinical Endocrinology & Metabolism (Oct. 2007) states that older men with low levels of testosterone may die sooner than other men their age with normal testosterone levels.

That means that 25% of men older than age 30 have a 40% increased risk of death due to low circulating androgen levels. I find this shocking. The question as to why this is occurring is speculative at best. Certainly, environmental endocrine disruptors and lifestyle both play a role.

Low testosterone levels in post-menopausal women are also associated with heart disease. Research published in the June 2007 edition of the European Journal of Endocrinology shows that higher testosterone levels in post-menopausal women may have a protective effect against cardiovascular disease. Researchers looked at 112 women, half of whom had atherosclerosis, which is seen as a precursor to major heart problems. Those with atherosclerosis had much less testosterone than those without. These researchers believe the hormone can suppress chemical signals that cause inflammation in the arterial wall.

Testosterone and its metabolites have diverse tissue effects. Through interactions with the androgen receptor (AR), testosterone affects muscle, bone, bone marrow and the brain. Via AR transcription effects and signaling pathways, exogenous testosterone may enhance muscle and bone strength, promote erythropoiesis and bolster patients’ energy levels, but may also increase the risk of erythrocytosis and/or sleep apnea.

We know that testosterone directly upregulates nitric oxide (NO) synthase in the endothelial cell. This is directly responsible for vasodilation action and endothelial health. When NO, the signaling molecule, enters a cell, it activates an enzyme called guanylate cyclase, which produces cyclic GMP, the second messenger. Cyclic GMP actually does the work of relaxing and dilating the blood vessels. In addition, NO functions to prevent heart disease and strokes in several ways: It helps preclude atherosclerosis by preventing platelets and white blood cells from sticking to the vessel wall. Under many conditions, NO reduces the production of free radicals, which can cause vessels to age rapidly. Further, it suppresses abnormal growth of vascular muscle cells that cause thickening of the vessels.

Testosterone replacement may be associated with clinical improvement of symptoms of coronary artery disease. Recent clinical studies reported that testosterone concentrations were inversely associated with intima media thickness and artery plaque score; inversely associated with the pro-inflammatory cytokine tumor-necrosis factor α (TNF-α) and positively associated with the anti-inflammatory cytokine interleukin-10 (IL-10) and with systemic arterial compliance; and did not negatively influence markers of coagulation.In fact, in one study testosterone concentrations were independently associated with degree of coronary artery disease, despite the finding that traditional risk factors for myocardial infarction were not.A placebo-controlled crossover study in men with ischemic heart disease and hypogonadism reported that with testosterone replacement therapy, the time to 1mm electrocardiographic ST segment depression increased, total cholesterol decreased, exercise time increased, symptoms of hypogonadism decreased and mood improved.

A recent clinical study reported that testosterone therapy reduces myocardial ischemia in men with cardiovascular disease, with beneficial modulation of coronary vascular tone by testosterone as a hypothesis. A placebo-controlled study found that 12 weeks of testosterone replacement therapy improved brachial artery vasoreactivity in men with coronary artery disease. Combined, these small studies provide preliminary evidence of possible clinical benefits of testosterone replacement therapy in men with coronary artery disease.

Testosterone replacement therapy may also be beneficial in men with chronic heart failure, as suggested by the findings of several small trials that reported increased cardiac index and decreased systemic vascular resistance, increased exercise capacity and symptomatic improvement by at least one New York Heart Association class and no significant change in TNF-α.

Part of the positive testosterone effects on a man’s cardiovascular system is due to the effects of the conversion of testosterone to estrogen by aromatase enzymes within the cardiovascular tissues. The two hormones, testosterone and estrogen, work together for positive effects.

Obviously, this does not mean that every man or woman should be placed on hormones. What it does mean is that appropriate assessment needs to be conducted. The other question to ask is: If we are not treating hormones and assessing patients’ levels, then how do we know if we are doing our job protecting patients from potential adverse effects of low hormones? Maintaining age-appropriate levels is the key.

Recognizing that low levels of androgens and steroidal precursors contribute to cardiovascular disease and osteoporosis, how do we not address this issue? A question that comes to mind is if we treat symptoms of menopause and do not address the underlying hormone levels, then we may not be protecting and acting in a preventive fashion. There are times when hormone administration should not be undertaken. Instead, a comprehensive naturopathic approach looking to support vital function and encourage endogenous production of hormones is the route. In other cases where age and/or circumstance pose an obstacle to cure, we must assess risk vs. benefit. Testosterone replacement therapy should not be administered to men with high or significantly increasing PSA levels.

Another interesting association is that of growth hormone (GH) deficiency and atherosclerosis. GH is involved not only in growth promotion in childhood but also in adjusting various metabolic factors such as lipids, protein and sugar. Recently, the importance of GH as a metabolic regulatory hormone in adulthood has been recognized, especially the fact that the death rate derived from cardiovascular system complication is high in adults with GH hyposecretion disease. There is a correlation to GH deficiency causing or accelerating atherosclerosis.

In conclusion, contrary to the view that testosterone and other hormones have a negative effect on the cardiovascular system, a view caused by the complications of illegal steroid abuse, recent evidence points to the beneficial effects of normal, age-appropriate levels of testosterone. There is some indication that restoring normal healthy levels of these hormones may be helpful in preventing heart disease.

Indications for CIMT Testing

  • 45 years of age or older
  • Family history of heart attack or stroke
  • Overweight
  • Smoking
  • High blood pressure
  • Diabetes
  • High cholesterol
  • Little or no exercise

handwergerBronner Handwerger, ND is the medical director of Wellness Kliniek, an integrative health center in San Diego. He served as medical director for the D’Adamo Clinic and as an assistant clinical professor at the University of Bridgeport Naturopathic Medical Center. In addition, Dr. Handwerger served as a panel member for the White House Commission on Complementary and Alternative Medicine. He enjoys working with a wide range of patients, and specializes in the naturopathic approach to endocrinology, oncology and internal medicine

References

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Jones RD et al: Testosterone and atherosclerosis in aging men: purported association and clinical implications, Am J Cardiovasc Drugs 5: 141-54, 2005.

Fukui M et al: Association between serum testosterone concentration and carotid atherosclerosis in men with type 2 diabetes, Diabetes Care 26: 1869-73, 2003.

Muller M et al: Endogenous sex hormones and progression of carotid atherosclerosis in elderly men, Circulation 109: 2074-9, 2004.

Malkin CJ et al: The effect of testosterone replacement on endogenous inflammatory cytokines and lipid profiles in hypogonadal men, J Clin Endocrinol Metab 89: 3313-8, 2004.

Dockery F et al: Testosterone suppression in men with prostate cancer leads to an increase in arterial stiffness and hyperinsulinaemia, Clin Sci (Lond) 104: 195-201, 2003.

Phillips GB et al: Are major risk factors for myocardial infarction the major predictors of degree of coronary artery disease in men?, Metabolism 53: 324-9, 2004.

Malkin CJ et al: Testosterone replacement in hypogonadal men with angina improves ischaemic threshold and quality of life, Heart 90: 871-6, 2004.

Jones RD et al: The influence of testosterone upon vascular reactivity, Eur J Endocrinol 151: 29-37, 2004.

Pugh PJ et al: Acute haemodynamic effects of testosterone in men with chronic heart failure, Eur Heart J 24: 909-15, 2003.

Institute of Medicine. Testosterone and Aging: Clinical Research Directions. Committee on Assessing the Need for Clinical Trials of Testosterone Replacement Therapy. Washington, DC, 2003, National Academies Press.

Araujo AB et al: Prevalence and incidence of androgen deficiency in middle-aged and older men: estimates from the Massachusetts Male Aging Study, J Clin Endocrinol Metab 89: 5920-6, 2004.

Mulligan T et al: Prevalence of hypogonadism in males aged at least 45 years: the HIM study, Int J Clin Pract 60: 762-9, 2006.

Szulc P et al: Increased risk of falls and increased bone resorption in elderly men with partial androgen deficiency: the MINOS study, J Clin Endocrinol Metab 88: 5240-7, 2003.

Dhindsa S et al: Frequent occurrence of hypogonadotropic hypogonadism in type 2 diabetes, J Clin Endocrinol Metab 89: 5462-8, 2004.

Kang SM et al: Effect of oral administration of testosterone on brachial arterial vasoreactivity in men with coronary artery disease, Am J Cardiol 89: 862-4, 2002.

Malkin CJ et al: Testosterone therapy in men with moderate severity heart failure: a double-blind randomized placebo controlled trial, Eur Heart J 27: 57-64, 2006.

Pugh PJ et al: Physiologic testosterone therapy has no effect on serum levels of tumor necrosis factor-alpha in men with chronic heart failure, Endocr Res 31: 271-83, 2005.

Bots, ML et al: Carotid intima-media thickness, arterial stiffness and risk of cardiovascular disease: current evidence, Journal of Hypertension 20(12):2317-2325, 2002.

Amato G et al: Recombinant growth hormone (GH) therapy in GH-deficient adults: a long-term controlled study on daily versus thrice weekly injections, J Clin Endocrinol Metab Oct;85(10):3786-92, 2000.

Debing E et al: Endogenous sex hormone levels in postmenopausal women undergoing carotid artery endarterectomy, Eur J Endocrinol 156:687-693, 2007.

Seftel A: Testosterone replacement therapy for male hypogonadism: part III. Pharmacologic and clinical profiles, monitoring, safety issues, and potential future agents, Int J Impot Res Jan-Feb;19(1):2-24, 2007.

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